Changing Clinical Epidemiology of Plasmodium vivax Malaria as Transmission Decreases: Population-Based Prospective Panel Survey in the Brazilian Amazon.

BACKGROUND: Malarial infections are often missed by microscopy, and most parasite carriers are asymptomatic in low-endemicity settings. Whether parasite detectability and its ability to elicit symptoms change as transmission declines remains unclear. METHODS: We performed a prospective panel survey with repeated measurements on the same participants over 12 months to investigate whether Plasmodium vivax detectability by microscopy and risk of symptoms upon infection varied during a community-wide larviciding intervention in the Amazon basin of Brazil that markedly reduced vector density. We screened 1096 to 1400 residents in the intervention site for malaria by microscopy and quantitative TaqMan assays at baseline and twice during intervention. RESULTS: We found that more P vivax infections than expected from their parasite densities measured by TaqMan assays were missed by microscopy as transmission decreased. At lower transmission, study participants appeared to tolerate higher P vivax loads without developing symptoms. We hypothesize that changes in the ratio between circulating parasites and those that accumulate in the bone marrow and spleen, by avoiding peripheral blood microscopy detection, account for decreased parasite detectability and lower risk of symptoms under low transmission. CONCLUSIONS: P vivax infections are more likely to be subpatent and remain asymptomatic as malaria transmission decreases.

Adolescent pregnancy in Cruzeiro do Sul, Acre, Brazil: socioeconomic characteristics, prenatal and obstetric care. / Parturientes adolescentes em Cruzeiro do Sul, Acre, Brasil: características socioeconômicas e obstétricas.

The present study aimed to investigate the socioeconomic and obstetric characteristics of adolescent mothers and the complications they cause to maternal and neonatal health. This baseline data analysis of the MINA-Brazil birth cohort was conducted in the municipality of Cruzeiro do Sul, state of Acre, Brazil. The chi-square test was used to compare characteristics of adolescent and adult postpartum women, and multiple Poisson regression models with robust variance were used to assess associated factors. Among the postpartum women, 26.2% (95%CI: 24.0-28.4) were adolescents. Factors associated with childbirth in adolescence included: nine years or less of schooling (adjPR:1.36; 95%CI: 1.14-1.61), belongs to the lowest quartiles of the wealth index (1st quartile: adjPR:1.40; 95%CI: 1.08-1.80) (2nd quartile: adjPR:1.37; 95%CI: 1.08-1.74), primigravidae (adjPR:3.69; 95%CI: 2.98-4.57), low pre-pregnancy BMI (adjPR:1.28; CI95%: 1.04-1.57), urinary tract infection during pregnancy (adjPR:1.25; CI95%: 1.07-1.46) and less than six prenatal consultations (adjPR:1.42; 95%CI: 1.21-1.66). Poverty, little schooling, primigravidae, low pre-pregnancy BMI, urinary tract infection during pregnancy and few prenatal consultations were associated with childbirth during adolescence in a municipality in the Northern region of Brazil.

O objetivo do estudo foi investigar as características socioeconômicas e obstétricas de parturientes adolescentes e suas complicações sobre a saúde materna e neonatal. Trata-se de uma análise de dados da linha de base da coorte de nascimentos MINA-Brasil conduzida no município de Cruzeiro do Sul, estado do Acre. Utilizou-se teste qui-quadrado para comparar características das puérperas adolescentes com as adultas e modelos múltiplos de regressão de Poisson com variância robusta para avaliar fatores associados. Entre as puérperas estudadas, 26,2% (IC95%: 24,0-28,4) eram adolescentes. Os fatores associados ao parto na adolescência foram ter nove anos ou menos de estudo (RPaj:1,36; IC95%: 1,14-1,61), pertencer aos menores quartis do índice de riqueza (1° quartil: RPaj:1,40; IC95%: 1,08-1,80) (2° quartil: RPaj:1,37; IC95%: 1,08-1,74), ser primigesta (RPaj:3,69; IC95%: 2,98-4,57), baixo IMC pré-gestacional (RPaj:1,28; IC95%: 1,04-1,57), infecção urinária na gravidez (RPaj:1,25; IC95%: 1,07-1,46) e menos de seis consultas de pré-natal (RPaj:1,42; IC95%: 1,21-1,66). Pobreza, baixa escolaridade, primigestação, baixo IMC pré-gestacional, infecção urinária na gestação e menor número de consultas de pré-natal foram associados ao parto na adolescência em município da região Norte do Brasil.

Effect of primaquine dose on the risk of recurrence in patients with uncomplicated Plasmodium vivax: a systematic review and individual patient data meta-analysis.

BACKGROUND: Primaquine is used to eliminate Plasmodium vivax hypnozoites, but its optimal dosing regimen remains unclear. We undertook a systematic review and individual patient data meta-analysis to investigate the efficacy and tolerability of different primaquine dosing regimens to prevent P vivax recurrence. METHODS: For this systematic review and individual patient data meta-analysis, we searched MEDLINE, Web of Science, Embase, and Cochrane Central for prospective clinical studies of uncomplicated P vivax from endemic countries published between Jan 1, 2000, and June 8, 2023. We included studies if they had active follow-up of at least 28 days, and if they included a treatment group with daily primaquine given over multiple days, where primaquine was commenced within 7 days of schizontocidal treatment and was given alone or coadministered with chloroquine or one of four artemisinin-based combination therapies (ie, artemether-lumefantrine, artesunate-mefloquine, artesunate-amodiaquine, or dihydroartemisinin-piperaquine). We excluded studies if they were on prevention, prophylaxis, or patients with severe malaria, or if data were extracted retrospectively from medical records outside of a planned trial. For the meta-analysis, we contacted the investigators of eligible trials to request individual patient data and we then pooled data that were made available by Aug 23, 2021. We assessed the effects of total dose and duration of primaquine regimens on the rate of first P vivax recurrence between day 7 and day 180 by Cox's proportional hazards regression (efficacy analysis). The effect of primaquine daily dose on gastrointestinal symptoms on days 5-7 was assessed by modified Poisson regression (tolerability analysis). The study was registered with PROSPERO, CRD42019154470. FINDINGS: Of 226 identified studies, 23 studies with patient-level data from 6879 patients from 16 countries were included in the efficacy analysis. At day 180, the risk of recurrence was 51·0% (95% CI 48·2-53·9) in 1470 patients treated without primaquine, 19·3% (16·9-21·9) in 2569 patients treated with a low total dose of primaquine (approximately 3·5 mg/kg), and 8·1% (7·0-9·4) in 2811 patients treated with a high total dose of primaquine (approximately 7 mg/kg), regardless of primaquine treatment duration. Compared with treatment without primaquine, the rate of P vivax recurrence was lower after treatment with low-dose primaquine (adjusted hazard ratio 0·21, 95% CI 0·17-0·27; p<0·0001) and high-dose primaquine (0·10, 0·08-0·12; p<0·0001). High-dose primaquine had greater efficacy than low-dose primaquine in regions with high and low relapse periodicity (ie, the time from initial infection to vivax relapse). 16 studies with patient-level data from 5609 patients from ten countries were included in the tolerability analysis. Gastrointestinal symptoms on days 5-7 were reported by 4·0% (95% CI 0·0-8·7) of 893 patients treated without primaquine, 6·2% (0·5-12·0) of 737 patients treated with a low daily dose of primaquine (approximately 0·25 mg/kg per day), 5·9% (1·8-10·1) of 1123 patients treated with an intermediate daily dose (approximately 0·5 mg/kg per day) and 10·9% (5·7-16·1) of 1178 patients treated with a high daily dose (approximately 1 mg/kg per day). 20 of 23 studies included in the efficacy analysis and 15 of 16 in the tolerability analysis had a low or unclear risk of bias. INTERPRETATION: Increasing the total dose of primaquine from 3·5 mg/kg to 7 mg/kg can reduce P vivax recurrences by more than 50% in most endemic regions, with a small associated increase in gastrointestinal symptoms. FUNDING: Australian National Health and Medical Research Council, Bill & Melinda Gates Foundation, and Medicines for Malaria Venture.

Primaquine dose and the risk of haemolysis in patients with uncomplicated Plasmodium vivax malaria: a systematic review and individual patient data meta-analysis.

BACKGROUND: Primaquine radical cure is used to treat dormant liver-stage parasites and prevent relapsing Plasmodium vivax malaria but is limited by concerns of haemolysis. We undertook a systematic review and individual patient data meta-analysis to investigate the haematological safety of different primaquine regimens for P vivax radical cure. METHODS: For this systematic review and individual patient data meta-analysis, we searched MEDLINE, Web of Science, Embase, and Cochrane Central for prospective clinical studies of uncomplicated P vivax from endemic countries published between Jan 1, 2000, and June 8, 2023. We included studies if they had active follow-up of at least 28 days, if they included a treatment group with daily primaquine given over multiple days where primaquine was commenced within 3 days of schizontocidal treatment and was given alone or coadministered with chloroquine or one of four artemisinin-based combination therapies (ie, artemether-lumefantrine, artesunate-mefloquine, artesunate-amodiaquine, or dihydroartemisinin-piperaquine), and if they recorded haemoglobin or haematocrit concentrations on day 0. We excluded studies if they were on prevention, prophylaxis, or patients with severe malaria, or if data were extracted retrospectively from medical records outside of a planned trial. For the meta-analysis, we contacted the investigators of eligible trials to request individual patient data and we then pooled data that were made available by Aug 23, 2021. The main outcome was haemoglobin reduction of more than 25% to a concentration of less than 7 g/dL by day 14. Haemoglobin concentration changes between day 0 and days 2-3 and between day 0 and days 5-7 were assessed by mixed-effects linear regression for patients with glucose-6-phosphate dehydrogenase (G6PD) activity of (1) 30% or higher and (2) between 30% and less than 70%. The study was registered with PROSPERO, CRD42019154470 and CRD42022303680. FINDINGS: Of 226 identified studies, 18 studies with patient-level data from 5462 patients from 15 countries were included in the analysis. A haemoglobin reduction of more than 25% to a concentration of less than 7 g/dL occurred in one (0·1%) of 1208 patients treated without primaquine, none of 893 patients treated with a low daily dose of primaquine (<0·375 mg/kg per day), five (0·3%) of 1464 patients treated with an intermediate daily dose (0·375 mg/kg per day to <0·75 mg/kg per day), and six (0·5%) of 1269 patients treated with a high daily dose (≥0·75 mg/kg per day). The covariate-adjusted mean estimated haemoglobin changes at days 2-3 were -0·6 g/dL (95% CI -0·7 to -0·5), -0·7 g/dL (-0·8 to -0·5), -0·6 g/dL (-0·7 to -0·4), and -0·5 g/dL (-0·7 to -0·4), respectively. In 51 patients with G6PD activity between 30% and less than 70%, the adjusted mean haemoglobin concentration on days 2-3 decreased as G6PD activity decreased; two patients in this group who were treated with a high daily dose of primaquine had a reduction of more than 25% to a concentration of less than 7 g/dL. 17 of 18 included studies had a low or unclear risk of bias. INTERPRETATION: Treatment of patients with G6PD activity of 30% or higher with 0·25-0·5 mg/kg per day primaquine regimens and patients with G6PD activity of 70% or higher with 0·25-1 mg/kg per day regimens were associated with similar risks of haemolysis to those in patients treated without primaquine, supporting the safe use of primaquine radical cure at these doses. FUNDING: Australian National Health and Medical Research Council, Bill & Melinda Gates Foundation, and Medicines for Malaria Venture.

Parturientes adolescentes em Cruzeiro do Sul, Acre, Brasil: características socioeconômicas e obstétricas / Adolescent pregnancy in Cruzeiro do Sul, Acre, Brazil: socioeconomic characteristics, prenatal and obstetric care

Resumo O objetivo do estudo foi investigar as características socioeconômicas e obstétricas de parturientes adolescentes e suas complicações sobre a saúde materna e neonatal. Trata-se de uma análise de dados da linha de base da coorte de nascimentos MINA-Brasil conduzida no município de Cruzeiro do Sul, estado do Acre. Utilizou-se teste qui-quadrado para comparar características das puérperas adolescentes com as adultas e modelos múltiplos de regressão de Poisson com variância robusta para avaliar fatores associados. Entre as puérperas estudadas, 26,2% (IC95%: 24,0-28,4) eram adolescentes. Os fatores associados ao parto na adolescência foram ter nove anos ou menos de estudo (RPaj:1,36; IC95%: 1,14-1,61), pertencer aos menores quartis do índice de riqueza (1° quartil: RPaj:1,40; IC95%: 1,08-1,80) (2° quartil: RPaj:1,37; IC95%: 1,08-1,74), ser primigesta (RPaj:3,69; IC95%: 2,98-4,57), baixo IMC pré-gestacional (RPaj:1,28; IC95%: 1,04-1,57), infecção urinária na gravidez (RPaj:1,25; IC95%: 1,07-1,46) e menos de seis consultas de pré-natal (RPaj:1,42; IC95%: 1,21-1,66). Pobreza, baixa escolaridade, primigestação, baixo IMC pré-gestacional, infecção urinária na gestação e menor número de consultas de pré-natal foram associados ao parto na adolescência em município da região Norte do Brasil.

Abstract The present study aimed to investigate the socioeconomic and obstetric characteristics of adolescent mothers and the complications they cause to maternal and neonatal health. This baseline data analysis of the MINA-Brazil birth cohort was conducted in the municipality of Cruzeiro do Sul, state of Acre, Brazil. The chi-square test was used to compare characteristics of adolescent and adult postpartum women, and multiple Poisson regression models with robust variance were used to assess associated factors. Among the postpartum women, 26.2% (95%CI: 24.0-28.4) were adolescents. Factors associated with childbirth in adolescence included: nine years or less of schooling (adjPR:1.36; 95%CI: 1.14-1.61), belongs to the lowest quartiles of the wealth index (1st quartile: adjPR:1.40; 95%CI: 1.08-1.80) (2nd quartile: adjPR:1.37; 95%CI: 1.08-1.74), primigravidae (adjPR:3.69; 95%CI: 2.98-4.57), low pre-pregnancy BMI (adjPR:1.28; CI95%: 1.04-1.57), urinary tract infection during pregnancy (adjPR:1.25; CI95%: 1.07-1.46) and less than six prenatal consultations (adjPR:1.42; 95%CI: 1.21-1.66). Poverty, little schooling, primigravidae, low pre-pregnancy BMI, urinary tract infection during pregnancy and few prenatal consultations were associated with childbirth during adolescence in a municipality in the Northern region of Brazil.

Effect of adherence to primaquine on the risk of Plasmodium vivax recurrence: a WorldWide Antimalarial Resistance Network systematic review and individual patient data meta-analysis.

BACKGROUND: Imperfect adherence is a major barrier to effective primaquine radical cure of Plasmodium vivax. This study investigated the effect of reduced adherence on the risk of P. vivax recurrence. METHODS: Efficacy studies of patients with uncomplicated P. vivax malaria, including a treatment arm with daily primaquine, published between January 1999 and March 2020 were identified. Individual patient data from eligible studies were pooled using standardized methodology. Adherence to primaquine was inferred from i) the percentage of supervised doses and ii) the total mg/kg dose received compared to the target total mg/kg dose per protocol. The effect of adherence to primaquine on the incidence of P. vivax recurrence between days 7 and 90 was investigated by Cox regression analysis. RESULTS: Of 82 eligible studies, 32 were available including 6917 patients from 18 countries. For adherence assessed by percentage of supervised primaquine, 2790 patients (40.3%) had poor adherence (≤ 50%) and 4127 (59.7%) had complete adherence. The risk of recurrence by day 90 was 14.0% [95% confidence interval: 12.1-16.1] in patients with poor adherence compared to 5.8% [5.0-6.7] following full adherence; p = 0.014. After controlling for age, sex, baseline parasitaemia, and total primaquine dose per protocol, the rate of the first recurrence was higher following poor adherence compared to patients with full adherence (adjusted hazard ratio (AHR) = 2.3 [1.8-2.9]). When adherence was quantified by total mg/kg dose received among 3706 patients, 347 (9.4%) had poor adherence, 88 (2.4%) had moderate adherence, and 3271 (88.2%) had complete adherence to treatment. The risks of recurrence by day 90 were 8.2% [4.3-15.2] in patients with poor adherence and 4.9% [4.1-5.8] in patients with full adherence; p < 0.001. CONCLUSION: Reduced adherence, including less supervision, increases the risk of vivax recurrence.

Molecular diversity of genes related to biological rhythms (period and timeless) and insecticide resistance (Na V and ace-1) in Anopheles darlingi.

BACKGROUND: Malaria is a public health concern in the Amazonian Region, where Anopheles darlingi is the main vector of Plasmodium spp. Several studies hypothesised the existence of cryptic species in An. darlingi, considering variations in behaviour, morphological and genetic aspects. Determining their overall genetic background for vector competence, insecticide resistance, and other elements is essential to better guide strategies for malaria control. OBJECTIVES: This study aimed to evaluate the molecular diversity in genes related to behaviour and insecticide resistance, estimating genetic differentiation in An. darlingi populations from Amazonian localities in Brazil and Pacific Colombian region. METHODS: We amplified, cloned and sequenced fragments of genes related to behaviour: timeless (tim) and period (per), and to insecticide resistance: voltage-gated sodium channel (Na V ) and acetylcholinesterase (ace-1) from 516 An. darlingi DNA samples from Manaus, Unini River, Jaú River and Porto Velho - Brazil, and Chocó - Colombia. We discriminated single nucleotide polymorphisms (SNPs), determined haplotypes and evaluate the phylogenetic relationship among the populations. FINDINGS: The genes per, tim and ace-1 were more polymorphic than Na V . The classical kdr and ace-1 R mutations were not observed. Phylogenetic analyses suggested a significant differentiation between An. darlingi populations from Brazil and Colombia, except for the Na V gene. There was a geographic differentiation within Brazilian populations considering per and ace-1. CONCLUSIONS: Our results add genetic data to the discussion about polymorphisms at population levels in An. darlingi. The search for insecticide resistance-related mechanisms should be extended to more populations, especially from localities with a vector control failure scenario.

Molecular diversity of genes related to biological rhythms (period and timeless) and insecticide resistance (Na V and ace-1) in Anopheles darlingi

BACKGROUND Malaria is a public health concern in the Amazonian Region, where Anopheles darlingi is the main vector of Plasmodium spp. Several studies hypothesised the existence of cryptic species in An. darlingi, considering variations in behaviour, morphological and genetic aspects. Determining their overall genetic background for vector competence, insecticide resistance, and other elements is essential to better guide strategies for malaria control. OBJECTIVES This study aimed to evaluate the molecular diversity in genes related to behaviour and insecticide resistance, estimating genetic differentiation in An. darlingi populations from Amazonian localities in Brazil and Pacific Colombian region. METHODS We amplified, cloned and sequenced fragments of genes related to behaviour: timeless (tim) and period (per), and to insecticide resistance: voltage-gated sodium channel (Na V ) and acetylcholinesterase (ace-1) from 516 An. darlingi DNA samples from Manaus, Unini River, Jaú River and Porto Velho - Brazil, and Chocó - Colombia. We discriminated single nucleotide polymorphisms (SNPs), determined haplotypes and evaluate the phylogenetic relationship among the populations. FINDINGS The genes per, tim and ace-1 were more polymorphic than Na V . The classical kdr and ace-1 R mutations were not observed. Phylogenetic analyses suggested a significant differentiation between An. darlingi populations from Brazil and Colombia, except for the Na V gene. There was a geographic differentiation within Brazilian populations considering per and ace-1. CONCLUSIONS Our results add genetic data to the discussion about polymorphisms at population levels in An. darlingi. The search for insecticide resistance-related mechanisms should be extended to more populations, especially from localities with a vector control failure scenario.

Relative contribution of low-density and asymptomatic infections to Plasmodium vivax transmission in the Amazon: pooled analysis of individual participant data from population-based cross-sectional surveys.

Background: Low-density and asymptomatic Plasmodium vivax infections remain largely undetected and untreated and may contribute significantly to malaria transmission in the Amazon. Methods: We analysed individual participant data from population-based surveys that measured P vivax prevalence by microscopy and polymerase chain reaction (PCR) between 2002 and 2015 and modelled the relationship between parasite density and infectiousness to vectors using membrane feeding assay data. We estimated the proportion of sub-patent (i.e., missed by microscopy) and asymptomatic P vivax infections and examined how parasite density relates to clinical manifestations and mosquito infection in Amazonian settings. Findings: We pooled 24,986 observations from six sites in Brazil and Peru. P vivax was detected in 6·8% and 2·1% of them by PCR and microscopy, respectively. 58·5% to 92·6% of P vivax infections were asymptomatic and 61·2% to 96·3% were sub-patent across study sites. P vivax density thresholds associated with clinical symptoms were one order of magnitude higher in children than in adults. We estimate that sub-patent parasite carriers are minimally infectious and contribute 12·7% to 24·9% of the community-wide P vivax transmission, while asymptomatic carriers are the source of 28·2% to 79·2% of mosquito infections. Interpretation: Asymptomatic P vivax carriers constitute a vast infectious reservoir that, if targeted by malaria elimination strategies, could substantially reduce malaria transmission in the Amazon. Infected children may remain asymptomatic despite high parasite densities that elicit clinical manifestations in adults. Funding: US National Institutes of Health, Fundação de Amparo à Pesquisa do Estado de São Paulo, and Belgium Development Cooperation.

High-throughput Plasmodium falciparum hrp2 and hrp3 gene deletion typing by digital PCR to monitor malaria rapid diagnostic test efficacy.

Most rapid diagnostic tests for Plasmodium falciparum malaria target the Histidine-Rich Proteins 2 and 3 (HRP2 and HRP3). Deletions of the hrp2 and hrp3 genes result in false-negative tests and are a threat for malaria control. A novel assay for molecular surveillance of hrp2/hrp3 deletions was developed based on droplet digital PCR (ddPCR). The assay quantifies hrp2, hrp3, and a control gene with very high accuracy. The theoretical limit of detection was 0.33 parasites/µl. The deletion was reliably detected in mixed infections with wild-type and hrp2-deleted parasites at a density of >100 parasites/reaction. For a side-by-side comparison with the conventional nested PCR (nPCR) assay, 248 samples were screened in triplicate by ddPCR and nPCR. No deletions were observed by ddPCR, while by nPCR hrp2 deletion was observed in 8% of samples. The ddPCR assay was applied to screen 830 samples from Kenya, Zanzibar/Tanzania, Ghana, Ethiopia, Brazil, and Ecuador. Pronounced differences in the prevalence of deletions were observed among sites, with more hrp3 than hrp2 deletions. In conclusion, the novel ddPCR assay minimizes the risk of false-negative results (i.e., hrp2 deletion observed when the sample is wild type), increases sensitivity, and greatly reduces the number of reactions that need to be run.

Monthly biological larviciding associated with a tenfold decrease in larval density in fish farming ponds and reduced community-wide malaria incidence in northwestern Brazil.

BACKGROUND: Larvicides are typically applied to fixed and findable mosquito breeding sites, such as fish farming ponds used in commercial aquaculture, to kill immature forms and thereby reduce the size of adult malaria vector populations. However, there is little evidence suggesting that larviciding may suppress community-wide malaria transmission outside Africa. Here, we tested whether the biological larvicide VectoMax FG applied at monthly intervals to fish farming ponds can reduce malaria incidence in Amazonian Brazil. METHODS: This study was carried out in Vila Assis Brasil (VAB; population 1700), a peri-urban malaria hotspot in northwestern Brazil with a baseline annual parasite incidence of 553 malaria cases per 1000 inhabitants. The intervention consisted of monthly treatments with 20 kg/ha of VectoMax FG of all water-filled fish ponds in VAB (n ranging between 167 and 170) with a surface area between 20 and 8000 m2, using knapsack power mistblowers. We used single-group interrupted time-series analysis to compare monthly larval density measurements in fish ponds during a 14-month pre-intervention period (September 2017-October 2018), with measurements made during November 2018-October 2019 and shortly after the 12-month intervention (November 2019). We used interrupted time-series analysis with a comparison group to contrast the malaria incidence trends in VAB and nearby nonintervention localities before and during the intervention. RESULTS: Average larval densities decreased tenfold in treated fish farming ponds, from 0.467 (95% confidence interval [CI], 0.444-0.490) anopheline larvae per dip pre-intervention (September 2017-October 2018) to 0.046 (95% CI, 0.041-0.051) larvae per dip during (November 2018-October 2019) and shortly after the intervention (November 2019). Average malaria incidence rates decreased by 0.08 (95% CI, 0.04-0.11) cases per 100 person-months (P < 0.0001) during the intervention in VAB and remained nearly unchanged in comparison localities. We estimate that the intervention averted 24.5 (95% CI, 6.2-42.8) malaria cases in VAB between January and December 2019. CONCLUSIONS: Regular larviciding is associated with a dramatic decrease in larval density and a modest but significant decrease in community-wide malaria incidence. Larviciding may provide a valuable complementary vector control strategy in commercial aquaculture settings across the Amazon.

Monitoring Plasmodium vivax resistance to antimalarials: Persisting challenges and future directions.

Emerging antimalarial drug resistance may undermine current efforts to control and eliminate Plasmodium vivax, the most geographically widespread yet neglected human malaria parasite. Endemic countries are expected to assess regularly the therapeutic efficacy of antimalarial drugs in use in order to adjust their malaria treatment policies, but proper funding and trained human resources are often lacking to execute relatively complex and expensive clinical studies, ideally complemented by ex vivo assays of drug resistance. Here we review the challenges for assessing in vivo P. vivax responses to commonly used antimalarials, especially chloroquine and primaquine, in the presence of confounding factors such as variable drug absorption, metabolism and interaction, and the risk of new infections following successful radical cure. We introduce a simple modeling approach to quantify the relative contribution of relapses and new infections to recurring parasitemias in clinical studies of hypnozoitocides. Finally, we examine recent methodological advances that may render ex vivo assays more practical and widely used to confirm P. vivax drug resistance phenotypes in endemic settings and review current approaches to the development of robust genetic markers for monitoring chloroquine resistance in P. vivax populations.

The risk of Plasmodium vivax parasitaemia after P. falciparum malaria: An individual patient data meta-analysis from the WorldWide Antimalarial Resistance Network.

BACKGROUND: There is a high risk of Plasmodium vivax parasitaemia following treatment of falciparum malaria. Our study aimed to quantify this risk and the associated determinants using an individual patient data meta-analysis in order to identify populations in which a policy of universal radical cure, combining artemisinin-based combination therapy (ACT) with a hypnozoitocidal antimalarial drug, would be beneficial. METHODS AND FINDINGS: A systematic review of Medline, Embase, Web of Science, and the Cochrane Database of Systematic Reviews identified efficacy studies of uncomplicated falciparum malaria treated with ACT that were undertaken in regions coendemic for P. vivax between 1 January 1960 and 5 January 2018. Data from eligible studies were pooled using standardised methodology. The risk of P. vivax parasitaemia at days 42 and 63 and associated risk factors were investigated by multivariable Cox regression analyses. Study quality was assessed using a tool developed by the Joanna Briggs Institute. The study was registered in the International Prospective Register of Systematic Reviews (PROSPERO: CRD42018097400). In total, 42 studies enrolling 15,341 patients were included in the analysis, including 30 randomised controlled trials and 12 cohort studies. Overall, 14,146 (92.2%) patients had P. falciparum monoinfection and 1,195 (7.8%) mixed infection with P. falciparum and P. vivax. The median age was 17.0 years (interquartile range [IQR] = 9.0-29.0 years; range = 0-80 years), with 1,584 (10.3%) patients younger than 5 years. 2,711 (17.7%) patients were treated with artemether-lumefantrine (AL, 13 studies), 651 (4.2%) with artesunate-amodiaquine (AA, 6 studies), 7,340 (47.8%) with artesunate-mefloquine (AM, 25 studies), and 4,639 (30.2%) with dihydroartemisinin-piperaquine (DP, 16 studies). 14,537 patients (94.8%) were enrolled from the Asia-Pacific region, 684 (4.5%) from the Americas, and 120 (0.8%) from Africa. At day 42, the cumulative risk of vivax parasitaemia following treatment of P. falciparum was 31.1% (95% CI 28.9-33.4) after AL, 14.1% (95% CI 10.8-18.3) after AA, 7.4% (95% CI 6.7-8.1) after AM, and 4.5% (95% CI 3.9-5.3) after DP. By day 63, the risks had risen to 39.9% (95% CI 36.6-43.3), 42.4% (95% CI 34.7-51.2), 22.8% (95% CI 21.2-24.4), and 12.8% (95% CI 11.4-14.5), respectively. In multivariable analyses, the highest rate of P. vivax parasitaemia over 42 days of follow-up was in patients residing in areas of short relapse periodicity (adjusted hazard ratio [AHR] = 6.2, 95% CI 2.0-19.5; p = 0.002); patients treated with AL (AHR = 6.2, 95% CI 4.6-8.5; p < 0.001), AA (AHR = 2.3, 95% CI 1.4-3.7; p = 0.001), or AM (AHR = 1.4, 95% CI 1.0-1.9; p = 0.028) compared with DP; and patients who did not clear their initial parasitaemia within 2 days (AHR = 1.8, 95% CI 1.4-2.3; p < 0.001). The analysis was limited by heterogeneity between study populations and lack of data from very low transmission settings. Study quality was high. CONCLUSIONS: In this meta-analysis, we found a high risk of P. vivax parasitaemia after treatment of P. falciparum malaria that varied significantly between studies. These P. vivax infections are likely attributable to relapses that could be prevented with radical cure including a hypnozoitocidal agent; however, the benefits of such a novel strategy will vary considerably between geographical areas.

Population genomics reveals the expansion of highly inbred Plasmodium vivax lineages in the main malaria hotspot of Brazil.

BACKGROUND: Plasmodium vivax is a neglected human malaria parasite that causes significant morbidity in the Americas, the Middle East, Asia, and the Western Pacific. Population genomic approaches remain little explored to map local and regional transmission pathways of P. vivax across the main endemic sites in the Americas, where great progress has been made towards malaria elimination over the past decades. METHODOLOGY/PRINCIPAL FINDINGS: We analyze 38 patient-derived P. vivax genome sequences from Mâncio Lima (ML)-the Amazonian malaria hotspot next to the Brazil-Peru border-and 24 sequences from two other sites in Acre State, Brazil, a country that contributes 23% of malaria cases in the Americas. We show that the P. vivax population of ML is genetically diverse (π = 4.7 × 10-4), with a high polymorphism particularly in genes encoding proteins putatively involved in red blood cell invasion. Paradoxically, however, parasites display strong genome-wide linkage disequilibrium, being fragmented into discrete lineages that are remarkably stable across time and space, with only occasional recombination between them. Using identity-by-descent approaches, we identified a large cluster of closely related sequences that comprises 16 of 38 genomes sampled in ML over 26 months. Importantly, we found significant ancestry sharing between parasites at a large geographic distance, consistent with substantial gene flow between regional P. vivax populations. CONCLUSIONS/SIGNIFICANCE: We have characterized the sustained expansion of highly inbred P. vivax lineages in a malaria hotspot that can seed regional transmission. Potential source populations in hotspots represent a priority target for malaria elimination in the Amazon.

Early determinants of linear growth and weight attained in the first year of life in a malaria endemic region.

We investigated linear growth and weight attained among 772 children at 10-15 months of age in the first population-based birth cohort in the Brazilian Amazon. Sociodemographic, maternal and birth characteristics were collected in interviews soon after birth at baseline. Anthropometric evaluation was conducted at 10-15 months. Multiple linear regression models were fitted for length-for-age (LAZ) and body mass index (BMI)-for-age Z scores (BAZ), considering a hierarchical conceptual framework with determinants at distal, intermediate and proximal levels, with adjustment for the child's sex and age. Mean LAZ and BAZ were 0.31 (SD: 1.13) and 0.35 (SD: 1.06), respectively. Overall, 2.2% of children were stunted and 6.6% overweight. Among socioeconomic factors, household wealth index was positively associated with LAZ (p for trend = 0.01), while children whose families received assistance from the Bolsa Família conditional cash transfer program were 0.16 Z score thinner (95% CI: -0.31, -0.00). Maternal height and BMI were positively associated with both LAZ and BAZ at 10-15 months of age (p for trend <0.001). Child's size at birth was positively related with LAZ (p<0.001 for both birth weight and length). BAZ was 0.34 (95% CI: 0.24, 0.44) higher, but 0.11 lower (95% CI: -0.21, -0.02), for each increase in 1 Z score of birth weight and length, respectively. Children with at least one reported malaria episode within the first year of life were 0.58 (95% CI: -1.05, -0.11) Z score shorter. Socioeconomic and intergenerational factors were consistently associated with LAZ and BAZ at 10-15 months of age. The occurrence of malaria was detrimental to linear growth. In a malaria endemic region, reduction of inequalities and disease burden over the first 1,000 days of life is essential for taking advantage of a critical window of opportunity that can redirect child growth trajectories toward better health and nutrition conditions in the long term.

Monitoring the Efficacy of Chloroquine-Primaquine Therapy for Uncomplicated Plasmodium vivax Malaria in the Main Transmission Hot Spot of Brazil.

Emerging Plasmodium vivax resistance to chloroquine (CQ) may undermine malaria elimination efforts in South America. CQ-resistant P. vivax has been found in the major port city of Manaus but not in the main malaria hot spots across the Amazon Basin of Brazil, where CQ is routinely coadministered with primaquine (PQ) for radical cure of vivax malaria. Here we randomly assigned 204 uncomplicated vivax malaria patients from Juruá Valley, northwestern Brazil, to receive either sequential (arm 1) or concomitant (arm 2) CQ-PQ treatment. Because PQ may synergize the blood schizontocidal effect of CQ and mask low-level CQ resistance, we monitored CQ-only efficacy in arm 1 subjects, who had PQ administered only at the end of the 28-day follow-up. We found adequate clinical and parasitological responses in all subjects assigned to arm 2. However, 2.2% of arm 1 patients had microscopy-detected parasite recrudescences at day 28. When PCR-detected parasitemias at day 28 were considered, response rates decreased to 92.1% and 98.8% in arms 1 and 2, respectively. Therapeutic CQ levels were documented in 6 of 8 recurrences, consistent with true CQ resistance in vivo In contrast, ex vivo assays provided no evidence of CQ resistance in 49 local P. vivax isolates analyzed. CQ-PQ coadministration was not found to potentiate the antirelapse efficacy of PQ over 180 days of surveillance; however, we suggest that larger studies are needed to examine whether and how CQ-PQ interactions, e.g., CQ-mediated inhibition of PQ metabolism, modulate radical cure efficacy in different P. vivax-infected populations. (This study has been registered at ClinicalTrials.gov under identifier NCT02691910.).

Human migration and the spread of malaria parasites to the New World.

We examined the mitogenomes of a large global collection of human malaria parasites to explore how and when Plasmodium falciparum and P. vivax entered the Americas. We found evidence of a significant contribution of African and South Asian lineages to present-day New World malaria parasites with additional P. vivax lineages appearing to originate from Melanesia that were putatively carried by the Australasian peoples who contributed genes to Native Americans. Importantly, mitochondrial lineages of the P. vivax-like species P. simium are shared by platyrrhine monkeys and humans in the Atlantic Forest ecosystem, but not across the Amazon, which most likely resulted from one or a few recent human-to-monkey transfers. While enslaved Africans were likely the main carriers of P. falciparum mitochondrial lineages into the Americas after the conquest, additional parasites carried by Australasian peoples in pre-Columbian times may have contributed to the extensive diversity of extant local populations of P. vivax.

Multi-criteria decision analysis and spatial statistic: an approach to determining human vulnerability to vector transmission of Trypanosoma cruzi

BACKGROUND Chagas disease (CD), caused by the protozoan Trypanosoma cruzi, is a neglected human disease. It is endemic to the Americas and is estimated to have an economic impact, including lost productivity and disability, of 7 billion dollars per year on average. OBJECTIVES To assess vulnerability to vector-borne transmission of T. cruzi in domiciliary environments within an area undergoing domiciliary vector interruption of T. cruzi in Colombia. METHODS Multi-criteria decision analysis [preference ranking method for enrichment evaluation (PROMETHEE) and geometrical analysis for interactive assistance (GAIA) methods] and spatial statistics were performed on data from a socio-environmental questionnaire and an entomological survey. In the construction of multi-criteria descriptors, decision-making processes and indicators of five determinants of the CD vector pathway were summarily defined, including: (1) house indicator (HI); (2) triatominae indicator (TI); (3) host/reservoir indicator (Ho/RoI); (4) ecotope indicator (EI); and (5) socio-cultural indicator (S-CI). FINDINGS Determination of vulnerability to CD is mostly influenced by TI, with 44.96% of the total weight in the model, while the lowest contribution was from S-CI, with 7.15%. The five indicators comprise 17 indices, and include 78 of the original 104 priority criteria and variables. The PROMETHEE and GAIA methods proved very efficient for prioritisation and quantitative categorisation of socio-environmental determinants and for better determining which criteria should be considered for interrupting the man-T. cruzi-vector relationship in endemic areas of the Americas. Through the analysis of spatial autocorrelation it is clear that there is a spatial dependence in establishing categories of vulnerability, therefore, the effect of neighbors' setting (border areas) on local values should be incorporated into disease management for establishing programs of surveillance and control of CD via vector. CONCLUSIONS The study model proposed here is flexible and can be adapted to various eco-epidemiological profiles and is suitable for focusing anti-T. cruzi serological surveillance programs in vulnerable human populations.

Multi-criteria decision analysis and spatial statistic: an approach to determining human vulnerability to vector transmission of Trypanosoma cruzi.

BACKGROUND: Chagas disease (CD), caused by the protozoan Trypanosoma cruzi, is a neglected human disease. It is endemic to the Americas and is estimated to have an economic impact, including lost productivity and disability, of 7 billion dollars per year on average. OBJECTIVES: To assess vulnerability to vector-borne transmission of T. cruzi in domiciliary environments within an area undergoing domiciliary vector interruption of T. cruzi in Colombia. METHODS: Multi-criteria decision analysis [preference ranking method for enrichment evaluation (PROMETHEE) and geometrical analysis for interactive assistance (GAIA) methods] and spatial statistics were performed on data from a socio-environmental questionnaire and an entomological survey. In the construction of multi-criteria descriptors, decision-making processes and indicators of five determinants of the CD vector pathway were summarily defined, including: (1) house indicator (HI); (2) triatominae indicator (TI); (3) host/reservoir indicator (Ho/RoI); (4) ecotope indicator (EI); and (5) socio-cultural indicator (S-CI). FINDINGS: Determination of vulnerability to CD is mostly influenced by TI, with 44.96% of the total weight in the model, while the lowest contribution was from S-CI, with 7.15%. The five indicators comprise 17 indices, and include 78 of the original 104 priority criteria and variables. The PROMETHEE and GAIA methods proved very efficient for prioritisation and quantitative categorisation of socio-environmental determinants and for better determining which criteria should be considered for interrupting the man-T. cruzi-vector relationship in endemic areas of the Americas. Through the analysis of spatial autocorrelation it is clear that there is a spatial dependence in establishing categories of vulnerability, therefore, the effect of neighbors' setting (border areas) on local values should be incorporated into disease management for establishing programs of surveillance and control of CD via vector. CONCLUSIONS: The study model proposed here is flexible and can be adapted to various eco-epidemiological profiles and is suitable for focusing anti-T. cruzi serological surveillance programs in vulnerable human populations.